Characterization of a disease in human patients
The goal of this assignment is to familiarize you with the process going from the characterization of a disease in human patients, to the identification of a mutated gene causing it, to the use of a mouse model to investigate how this mutation is causing the disease. You will learn about the spinocerebellar ataxia 1 (SCA1) genetic disease as an example of such a process.
This assignment is inspired by and uses content from, the lecture “A Healthy Nervous System: A Delicate Balance” https://www.biointeractive.org/professional-learning/science-talks/healthy-nervous-system-delicate-balance on BioInteractive. Watch the video, (it may also be useful to download the transcript https://www.biointeractive.org/sites/default/files/Cancer%2520and%2520Neuroscience%2520Lecture%25203%2520Transcript.pdf for reference) and answer the questions below.
Question 1: Based on this video, describe the symptoms of the SCA1 disease.
SCA1 is a familial disease as indicated by the pedigree analysis chart shown on the video
Question 2: Explain how to read the chart by indicating what the squares and circles represent and what is the difference between filled and hollow shapes.
Question 3: Discuss what conclusions can be drawn from the pedigree eg assuming that the disease is caused by the mutation of one single gene, do you think this mutation is recessive or dominant? Are the affected individuals more likely to be heterozygous or homozygous for this mutation? Is the disease affecting equally men and women? For each conclusion, make sure to explain how it is supported by the pedigree.
The Online Mendelian Inheritance in Man (OMIM) database https://omim.org/ is a frequently updated database of human genes and genetic diseases. Search for SCA1 on OMIM. Read quickly through the page to get a general idea of the types of information that can be found on it and how they are presented. Identify the gene whose mutation is responsible for the SCA1 disease, search for it on OMIM and have a quick look at the corresponding page.
Question 4: Based on the descriptions in OMIM and the information from the video, indicate what genetic mutation is responsible for the SCA1 disease and what consequence it has on protein primary structure.
Question 5: Which organ and cell type are primarily affected by the mutation? Is this consistent with the symptoms observed in SCA1 patients?
Mice are generally a good model for human diseases, if you wish, you can read more about the benefits of the mouse model on The Jackson Laboratory website Advantages of the mouse as a model organism. https://www.jax.org/why-the-mouse/genetics
Mouse models of SCA1 have been developed and helped researchers to understand this disease and to experiment new treatments.
Question 6: From the video describe the phenotype of the SCA1 mouse. Is it similar to symptoms observed in SCA1 patients?
Question 7: Is SCA1 considered to be caused by a loss of function of the protein affected, or is it thought to be due to another mechanism?
Question 8: Based on the findings from the mouse model, researchers then developed an SCA1 model in Drosophila – what are the advantages of using a Drosophila model over a mouse one
Question 9: Using the Drosophila model of SCA1, what was the protein kinase they found to be implicated in SCA1 associated neurodegeneration and why is this knowledge useful with respect to treating the disease?
Sample Solution
Spinocerebellar ataxia type 1 (SCA1) is a genetic disorder that affects the part of the brain responsible for coordination and movement. It is characterized by a gradual deterioration of physical coordination, balance, posture, gait and speech. Patients with SCA1 may experience difficulty walking or standing due to an inability to maintain balance; they may become unsteady on their feet or fall over more easily than usual. Additionally, affected individuals often have slurred speech as well as difficulty in swallowing food or liquids which can lead to choking episodes.
Additional symptoms associated with this condition include muscle twitches (myoclonus), poor hand control, irritability, depression and cognitive impairment such as memory loss and decreased concentration. In addition to these physical symptoms , patients may also suffer from sleep disturbances such as insomnia or excessive daytime sleepiness . Over time , these symptoms can worsen leading to complete loss of motor function .
While SCA1 primarily affects the neurological system it can also cause damage in other parts of the body – specifically in organs like the heart and lungs due to heavy skeletal muscle wasting caused by deteriorating nerve cells throughout the body (National Ataxia Foundation 2017). [1] SCA1 usually begins gradually between ages 10-20 but could manifest earlier depending on severity. There is no known cure for this disease but its progression might be slowed down through medication and lifestyle interventions such as physiotherapy
